Friday, June 8, 2012

Concurrent Session - Bariatric Medicine

Co-Chairs: Drs. Maria Tiboni, Stephen Glazer

Genetics and Obesity: Review of the Evidence

The increased prevalence of overweight and obesity observed worldwide and the realization that some forms of obesity were associated with higher risks than others for various morbid conditions and mortality rate have raised interest for research in the genetic and non-genetic causes of obesity. The objective of this presentation is to present a brief overview of the evidence for a role of genetic factors in obesity. In a genetic perspective, it is important to recognize that obesity is not a homogeneous phenotype and that strictly speaking one should talk of obesities rather than obesity. Thus, although the body mass index (BMI) is commonly used in clinical settings to assess the normality of body weight in patients, the BMI should not be considered a valid measure of adiposity or total body fatness. It is therefore not surprising to observe that the heritability of obesity varies depending of the obesity phenotype. Results from family and twin studies have clearly established that obesity runs in families and is partly heritable. The risk of obesity is about 2-10 times higher for individuals with a family history of obesity and the higher risks are observed for morbid obesity. Various designs such twin, family or adoption studies can be used to assess the relative contribution of genetic versus common familial environmental factors in explaining the familial resemblance of obesity. In general, heritability estimates are highest with twin studies (50%-70%), intermediate with family studies (25-50%) and lowest when derived from adoption data (10-30%) and tend to be higher for phenotypes indexing fat distribution and abdominal fat than for those indexing total body fatness. Eating and physical activity habits, the main lifestyle correlates of obesity, are themselves partly influenced by genetic factors, which suggests that some of the genetic influences on obesity may be attributable to the effects of genes influencing eating and/or physical activity habits. While our changing environment favouring increased food intake and decreased physical activity has clearly contributed to the shifting of the BMI at the population level, not everyone is becoming obese, which clearly suggests that there are genetic factors interacting with environmental factors to predispose individuals to obesity. Evidence suggests that this gene-environment interaction is not only important in determining an individual’s susceptibility to obesity, but can also influence the weight loss to various obesity treatments, including surgery. A large number of genes potentially associated with the susceptibility to obesity have been identified, but owing to the polygenic nature of obesity most of the genes identified were found to have small effects size. The identification of obesity genes increased considerably in the past 5 years through genome-wide association (GWA) studies, an approach that allows scanning the whole genome with hundreds of thousands of genetic variants and test their associations with the phenotype or disease of interest. Using that approach, the Fat Mass and Obesity Associated gene (FTO) was identified as the first obesity gene robustly and consistently associated with common forms of obesity. Despite the immense progress made in understanding the genetic and molecular basis of obesity, we should recognized that most of the genes identified so far have small effects size and may not have a causal role, which limits their predictive value. More research is needed to identify new genes using good measures of the relevant phenotypes and of environmental factors to better understand how they interact to determine an individual’s susceptibility to obesity.

Learning objectives

• The phenotype investigated is an important source of heterogeneity in genetic studies of obesity.
• Obesity is characterized by familial aggregation and the familial risk increases with the severity of obesity.
• Obesity is heritable and the heritability varies according to the phenotype being investigated, the design used for it’s estimation and the population.
• Eating and physical activity habits, the main lifestyle determinants of obesity, are influenced by genetic factors.
• Interaction between genes and environment play an important role in determining genetic susceptibility to obesity and the response to obesity treatment, including surgery.
• A large number of obesity genes have been identified, but most of them have small effects size.
• Good measures of the relevant phenotype and environmental exposures are essential to elucidate the genetic basis of obesity

Speaker